US20030018222A1 - Process of obtaining compositions of stable lutein and lutein derivatives - Google Patents
Process of obtaining compositions of stable lutein and lutein derivatives Download PDFInfo
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- US20030018222A1 US20030018222A1 US10/058,827 US5882702A US2003018222A1 US 20030018222 A1 US20030018222 A1 US 20030018222A1 US 5882702 A US5882702 A US 5882702A US 2003018222 A1 US2003018222 A1 US 2003018222A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/24—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by six-membered non-aromatic rings, e.g. beta-carotene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- Lutein is a carotenoid found in fruits and vegetables which has begun to acquire importance as a nutraceutical because of its antioxidant and immunomodulating/immunostimulating actions. These actions are manifested in its ability to reduce oxidative stress and/or depression of the immune system, in conditions such as age-related macular degeneration, cataracts, atherosclerosis, and some forms of cancer. Also, because of its yellow to red coloration and natural occurrence in human foods, lutein also is used as a food colorant.
- Lutein suitable for nutraceutical and cosmetic uses can be found in the chromoplasts of flowers, fruits and roots (such as, but not limited to, carrots and yellow potatoes). Lutein is typically present in plant chromoplasts as long chain fatty esters, typically diesters, of acids such as palmitic and myristic acids, e.g. lutein dipalminate, lutein dimyristate and lutein monomyristate. It has also been noted that once lutein is isolated from the plant, the lutein is biologically active in either the ester form or in the free form.
- U.S. Pat. No. 5,382,714 discloses a method of isolating, purifying and recrystallizing substantially pure lutein, preferably from saponified marigold oleoresin in its pure free form, apart from chemical impurities and other carotenoids. It also discloses that as of the filing of the '714 patent, pure lutein suitable for human use had not been commercially available for use as a chemopreventative agent in clinical trials. It was also noted that pure lutein which is free of chemical contaminant is necessary to design and conduct proper human intervention studies.
- the '714 patent disclosed a method of removing the lutein from the marigold petals without the chemical impurities.
- This method is disclosed as comprising the purification, preferably of a saponified marigold extract through the use of a series of filtrations and water/alcohol washes to obtain crude lutein crystals. These crystals are then dissolved in a halogenated organic solvent in which lutein is strongly soluble and then in a second organic solvent in which lutein is only partly soluble. This mixture is then cooled and the lutein is recrystallized in a high purity and it is then filtered and dried under vacuum.
- U.S. Pat. No. 5,648,564 discloses a process for forming, isolating and purifying xanthophyll crystals, preferably lutein, from marigold flower petals. It further disclosed that a xanthophyll diester-containing plant extract is saponified in a composition of propylene glycol and aqueous alkali to form xanthophyll crystals. It was also stated that the crystallization is achieved without the use of added organic solvents. The resulting crystals are then isolated and purified to produce substantially pure xanthophyll crystals suitable for human consumption.
- the '564 patent also noted that the claimed method had several advantages over the prior art, including its ability to produce luteins suitable for human consumption without using relatively toxic organic solvents during the isolation or crystallization steps. Additionally, the method does not require a recrystallization step.
- U.S. Pat. No. 4,048,203 discloses a process for the purification of lutein-fatty acid esters from marigold flower petals or marigold petal oleoresins based on alkanol precipitation.
- U.S. Pat. No. 6,007,856 discloses oil-in-water dispersions of ⁇ -carotene and other carotenoids that are stable against oxidation.
- the dispersions are prepared from water-dispersible beadlets comprising higher concentrations of colloidal ⁇ -carotene.
- U.S. Pat. No. 3,998,753 discloses water dispersible carotenoid compositions in liquid or powder form which can be incorporated into pharmaceuticals, cosmetic preparations or animal foodstuffs. It also discloses the processes of preparing these dispersible cartenoid compositions.
- U.S. Pat. No. 4,929,774 discloses a stable mixture of an oxidation-sensitive compound which also comprises triglycerides, complexing agents and coating substances.
- U.S. Pat. No. 5,536,504 discloses methods for treating tumors with ultramicroemulsions from spontaneously dispersible concentrates containing xanthophyll esters, and new esters with xanthophyll compounds. Further, methods for the production of the concentrates are also disclosed.
- This invention relates to methods of producing lutein and lutein derivatives in a stable form as well as the individual compounds. Additionally, the invention is directed towards specific lutein derivatives which possess a long storage life.
- antioxidant vitamins and/or beadlets Prior to the discoveries of this invention, those of ordinary skill used antioxidant vitamins and/or beadlets to stabilize lutein. These previously used methods primarily prevented the oxidation and the chemical and biological degradation of the lutein.
- One way in which the present invention is novel is that its stabilization of lutein and its esters goes beyond preventing oxidation.
- the present invention not only prevents oxidation of lutein and lutein esters, it also protects the lutein compound from destabilizing factors such as oxidants, temperature, humidity, daylight, and UV rays (hereinafter “other factors”) by obtaining lutein and lutein esters which protect against the other factors.
- the present invention provides a method of protecting lutein against direct and indirect physical, chemical, and biological factors which contribute to the deterioration of lutein and lutein esters.
- This method protects lutein and lutein esters from both xenobiotic compounds and the environmental elements.
- the totality of the protective action of the method is referred to hereinafter as XENOGARD (see Table I).
- the method of the present invention is two-fold. It is based on a unique process of isolation, which provides lutein and lutein esters chemically and less physically stressed in their isolated forms. The resulting product of the XENOGARD method is also more resistant to chemical/biological deterioration.
- the invention provides a method of combining lutein and lutein esters with at least one stabilizing compound, such as, but not limited to, 0.01-10 wt % tetrahydrocurcuminoids, 0.01-10 wt % of curcuminoids, or 0.01-10 wt % camosic acid.
- at least one stabilizing compound such as, but not limited to, 0.01-10 wt % tetrahydrocurcuminoids, 0.01-10 wt % of curcuminoids, or 0.01-10 wt % camosic acid.
- curcuminoids and curcuminoids are phenolic in nature, and that they are also recognized as antioxidants which provide protection against free radicals and also prevent the generation of free radicals. Additionally, curcuminoids are known to absorb UV rays and to protect pharmaceutical preparations from physio-chemical deterioration. Curcuminoids have also been found to prevent pyrolysis which is the high temperature related deterioration of processed food and nutrients. Curcuminoids are also recognized for their anti-microbial properties in preventing the growth of bacteria or fungi, which is a factor that is detrimental to the stability of lutein and lutein esters especially in humid conditions.
- Tetracurcuminoids which are derivatives of curcuminoids, are particularly effective in scavenging free radicals and are also complementary to the action of curcuminoids which are primarily effective in preventing free radicals from occurring in biological systems.
- Carnosic acid is compatible and complementary with both curcuminoids and tetracurcuminoids. It is an antioxidant and anti-microbial compound similar to curcuminoids and tetracurcuminoids' broad action consisting of free radical prevention and scavenging action.
- the process of obtaining XENOGARD lutein and lutein esters proceeds as follows. First, marigold flower petals are harvested. These petals are then shade dried, crushed and left at room temperature for a period of time, preferably 3 to 4 hours. The resulting material is then treated with a solvent, preferably an alcohol, and more preferably ethyl alcohol, and incubated, preferably for 5 hours at room temperature. A preferable ratio of solvent to marigold flower petals is 100 kg of the marigold material to 400 L of ethyl alcohol. Following the incubation period, the resulting solution is collected. This procedure is then repeated, preferably at least two additional times, and the combined alcohol extracts are combined. If the process is repeated two times and the preferred ratio is used then the total solution should amount to about 1250 L. The extracts are then diluted with water to obtain an alcohol solution, which is preferably 70% by weight alcohol.
- the shade dried petals can be treated with supercritical carbon dioxide for a period of time, preferably 10 hours, and after the evaporation of the carbon dioxide occurs, the remaining oleoresin is diluted with an alcohol, preferably ethanol, and water, as described above, to obtain a diluted alcohol solution, preferably a 70% alcohol solution.
- an alcohol preferably ethanol, and water, as described above, to obtain a diluted alcohol solution, preferably a 70% alcohol solution.
- This extract of marigold petals in the alcohol solution may then used to obtain lutein esters or free lutein by subjecting the extract to hydrolysis.
- This process entails passing the oleoresin in the alcohol solution through a column packed with an anion exchange resin. Preferably, this is performed at a rate of 20-50 L per hour.
- Suitable resins include Amberjet 4200(c), Amberlite IRA 410, Amberlite IRA 900, Dowex 1x2-100, Dowex 22cl, Dowex Marathon A2, Dowex MSA 1, Dowex 550 A, all of which are Rohm-Haas or Dow products.
- lutein crystals or lutein esters can be combined subsequent to their isolation with a stabilizing mixture of tetrahydrocurcuminoids in an amount of 0.01-10.0 wt %, curcuminoids in an amount of 0.01-10.0 wt %, and carsonic acid in an amount of 0.01-10.0 wt % to form the XENOGARD composition.
- a stabilizing mixture of tetrahydrocurcuminoids in an amount of 0.01-10.0 wt %
- curcuminoids in an amount of 0.01-10.0 wt %
- carsonic acid in an amount of 0.01-10.0 wt %
- each of the stabilizing ingredients are present in an amount of 0.1 wt. %.
- the XENOGARD composition of lutein or esters of lutein are then packaged under nitrogen atmosphere, sealed, and stored until further use.
- An additional XENOGARD compositions of lutein and lutein esters can be prepared in the form of a soft extract comprising at least 50 wt % marigold oleoresin, 45 wt % vegetable oil (preferably refined Soya oil), 1.5 wt % citric acid, and 2 wt % natural tocopherol.
- the XENOGARD lutein and lutein esters can be further stabilized by a coating process.
- An example of such a coating process would involve combining a sugar, preferably sucrose, preferably in as slurry form, with water (preferably distilled water) and the XENOGARD composition to obtain a uniform blend.
- the ratio used in forming the uniform blend would entail 450 g of sucrose to 100 ml of distilled water to 250 mg of the XENOGARD composition.
- Starch is then added to the uniform blend and the resulting mixture is then charged to a mixer which is run until the mixture is blended, preferably 30 minutes.
- the preferred ratio used in determining the appropriate amount of starch to add is 630 g of starch to 800 g of the uniform blend.
- PVP preferably in a ratio 450 g to 1430 g of starch solution
- a solvent preferably 70% ethanol solution
- the dough is then fed into a granulator preferably fitted with a 30 mesh screen and the granules are collected in trays which have been preferably lubricated with talc and dried under a vacuum for 8-12 hours.
- the dried granules are then transferred to a coating pan (suitably approximately 350 g of PVP and 40 g of paprika resin).
- a coating pan suitable approximately 350 g of PVP and 40 g of paprika resin.
- the resulting granules are dried again under vacuum at 30° C. for about 6-8 hours, and sifted and packed.
- FIG. 1 proves Zealutein®'s antioxidant activities
- FIGS. 2 and 3 illustrate its stability in two different forms. Further, it has been shown that the Zealutein® Regular Granules are stable for three years under normal conditions, whereas Zealutein® BJ-80 Mesh is stable for two years under normal conditions. The composition of both of these forms of Zealutein® are disclosed in FIGS. 4 and 5.
- the final composition of Zealutein® comprises lutein in an amount not less than 5 weight percent of the final product, Zeaxanthin in an amount not less than 1 weight percent of the final product, Piperine (and prefereably Bioperin®) in an amount not less than 2 weight percent of the final product, and other carotenoids in an amount not less than 1 weight percent of the final product.
- stabilizing components which may be used in the present invention include other carotenoids in the form of Capsanthin ester, Capsorubin ester, Zeaxanthin ester, Cryptoxanthin exter, and beta-carotene ester. These stabilizing components may be 1-10 weight percent of the final product. Additionally, paprika carotenoids are a potential source of stabilizing components, provided the paprika carotenoids are in the form of esters. Additions to the stabilizing components may also be added. These added compounds include tetracurcuminoids, Rosmarinic acid, green tea catechins and other similar natural antioxidants.
- FIG. 1 illustrates the Rancimat testing of Zealutein® and shows that Zealutein® possesses antioxidant properties.
- FIG. 2 illustrates a comparison of Zealutein® Regular Granules against lutein in which the stability of each has been tested at 30 day intervals in conditions of 40° C. and 75% relative humidity.
- FIG. 3 illustrates a comparison of Zealuteine BJ-80 Mesh against lutein in which the stability of each has been tested at 30 day intervals in conditions of 40° C. and 75% relative humidity.
- FIG. 4 lists the requirements and composition for Zealuteine BJ-80 Mesh.
- FIG. 5 lists the requirements and composition for Zealutein® Regular Granules.
- FIG. 6 illustrates the results of testing the effect of a topical application of zealutein on 12 O-tetradecanoylphorbol-13-acetate (TPA)-induced edema of mouse ears.
- TPA O-tetradecanoylphorbol-13-acetate
- FIG. 7 illustrates the dramatic difference in the percent of mice with cancer when being treated with a topical application of TPA when one group is treated with TPA alone and another is treated with TPA and zealutein.
- FIG. 8 illustrates the results of testing the inhibitory effect of zealutein on 12 O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor promotion in CD-1 mice previously initiated with 7,12-dimethylbenz[a]anthracene (DBMA).
- TPA O-tetradecanoylphorbol-13-acetate
- DBMA 7,12-dimethylbenz[a]anthracene
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Abstract
Description
- This application claims the benefit of U.S. Provisional Application No. 60/264,722, filed Jan. 30, 2001.
- Lutein is a carotenoid found in fruits and vegetables which has begun to acquire importance as a nutraceutical because of its antioxidant and immunomodulating/immunostimulating actions. These actions are manifested in its ability to reduce oxidative stress and/or depression of the immune system, in conditions such as age-related macular degeneration, cataracts, atherosclerosis, and some forms of cancer. Also, because of its yellow to red coloration and natural occurrence in human foods, lutein also is used as a food colorant.
- Lutein suitable for nutraceutical and cosmetic uses can be found in the chromoplasts of flowers, fruits and roots (such as, but not limited to, carrots and yellow potatoes). Lutein is typically present in plant chromoplasts as long chain fatty esters, typically diesters, of acids such as palmitic and myristic acids, e.g. lutein dipalminate, lutein dimyristate and lutein monomyristate. It has also been noted that once lutein is isolated from the plant, the lutein is biologically active in either the ester form or in the free form.
- Additionally, the highly unsaturated unconjugated chain of caroteinoids that makes up lutein is very sensitive to air, oxidizing agents, reducing agents, and structural alterations. Therefore, the loss of lutein during storage is well known. Further, lutein loss has been shown to begun as early as the raw material handling stage of the process. It has been documented that under carefully controlled conditions exposure to white fluorescent light resulted in the degradation of lutein in the range of 0.8-10.7% per day (please see Nahrung, 44, 38-41). However, ascorbic acid, an alkaline pH, low temperature (4° C.) and darkness were found to retard the degradation of carotenoids, including lutein (please see Akad. Nauk. SSSR., 127, 1128-1131; Chem Abstr., 54, 11162). It has also been discovered that lutein and lutein esters are not stable compounds at room temperature or higher, and that free lutein is especially vulnerable to chemical and biological deterioration.
- The preparation of stable and biologically active lutein and/or its esters from natural sources, such as Marigold petals, presents a challenging task. As seen in the following discussion, many patents have been issued on a method of obtaining such esters and the composition of the same.
- U.S. Pat. No. 5,382,714 (hereinafter the “'714 patent”) discloses a method of isolating, purifying and recrystallizing substantially pure lutein, preferably from saponified marigold oleoresin in its pure free form, apart from chemical impurities and other carotenoids. It also discloses that as of the filing of the '714 patent, pure lutein suitable for human use had not been commercially available for use as a chemopreventative agent in clinical trials. It was also noted that pure lutein which is free of chemical contaminant is necessary to design and conduct proper human intervention studies.
- The '714 patent noticed that esterified luteins are found with fatty acids in marigold petals, and that lutein could be produced upon saponification of the marigold lutein esters. However, the resulting lutein product was impure as it was contaminated with numerous chemical impurities.
- The '714 patent disclosed a method of removing the lutein from the marigold petals without the chemical impurities. This method is disclosed as comprising the purification, preferably of a saponified marigold extract through the use of a series of filtrations and water/alcohol washes to obtain crude lutein crystals. These crystals are then dissolved in a halogenated organic solvent in which lutein is strongly soluble and then in a second organic solvent in which lutein is only partly soluble. This mixture is then cooled and the lutein is recrystallized in a high purity and it is then filtered and dried under vacuum.
- U.S. Pat. No. 5,648,564 (hereinafter the “'564 patent”) discloses a process for forming, isolating and purifying xanthophyll crystals, preferably lutein, from marigold flower petals. It further disclosed that a xanthophyll diester-containing plant extract is saponified in a composition of propylene glycol and aqueous alkali to form xanthophyll crystals. It was also stated that the crystallization is achieved without the use of added organic solvents. The resulting crystals are then isolated and purified to produce substantially pure xanthophyll crystals suitable for human consumption.
- The '564 patent also noted that the claimed method had several advantages over the prior art, including its ability to produce luteins suitable for human consumption without using relatively toxic organic solvents during the isolation or crystallization steps. Additionally, the method does not require a recrystallization step.
- U.S. Pat. No. 4,048,203 (hereinafter the “'203 patent”) discloses a process for the purification of lutein-fatty acid esters from marigold flower petals or marigold petal oleoresins based on alkanol precipitation.
- U.S. Pat. No. 6,007,856 (hereinafterthe “'856 patent”) discloses oil-in-water dispersions of β-carotene and other carotenoids that are stable against oxidation. The dispersions are prepared from water-dispersible beadlets comprising higher concentrations of colloidal β-carotene.
- U.S. Pat. No. 3,998,753 (hereinafter the “'753 patent”) discloses water dispersible carotenoid compositions in liquid or powder form which can be incorporated into pharmaceuticals, cosmetic preparations or animal foodstuffs. It also discloses the processes of preparing these dispersible cartenoid compositions.
- U.S. Pat. No. 4,929,774 (hereinafter the “'774 patent”) discloses a stable mixture of an oxidation-sensitive compound which also comprises triglycerides, complexing agents and coating substances.
- U.S. Pat. No. 5,536,504 (hereinafter the “'504 patent”) discloses methods for treating tumors with ultramicroemulsions from spontaneously dispersible concentrates containing xanthophyll esters, and new esters with xanthophyll compounds. Further, methods for the production of the concentrates are also disclosed.
- This invention relates to methods of producing lutein and lutein derivatives in a stable form as well as the individual compounds. Additionally, the invention is directed towards specific lutein derivatives which possess a long storage life.
- Prior to the discoveries of this invention, those of ordinary skill used antioxidant vitamins and/or beadlets to stabilize lutein. These previously used methods primarily prevented the oxidation and the chemical and biological degradation of the lutein. One way in which the present invention is novel is that its stabilization of lutein and its esters goes beyond preventing oxidation. The present invention not only prevents oxidation of lutein and lutein esters, it also protects the lutein compound from destabilizing factors such as oxidants, temperature, humidity, daylight, and UV rays (hereinafter “other factors”) by obtaining lutein and lutein esters which protect against the other factors. It is also noted that these factors effect the stability of lutein and lutein esters during the extraction process, as well as the industrial processing of the same for use in final products. Finally, it was noted that vitamin-based antioxidants can prevent the deterioration of lutein, but it was not known whether they would be effective against the other factors.
- The present invention provides a method of protecting lutein against direct and indirect physical, chemical, and biological factors which contribute to the deterioration of lutein and lutein esters. This method protects lutein and lutein esters from both xenobiotic compounds and the environmental elements. The totality of the protective action of the method is referred to hereinafter as XENOGARD (see Table I). The method of the present invention is two-fold. It is based on a unique process of isolation, which provides lutein and lutein esters chemically and less physically stressed in their isolated forms. The resulting product of the XENOGARD method is also more resistant to chemical/biological deterioration. Additionally, the invention provides a method of combining lutein and lutein esters with at least one stabilizing compound, such as, but not limited to, 0.01-10 wt % tetrahydrocurcuminoids, 0.01-10 wt % of curcuminoids, or 0.01-10 wt % camosic acid.
- It should be noted that tetrahydrocurcuminoids and curcuminoids are phenolic in nature, and that they are also recognized as antioxidants which provide protection against free radicals and also prevent the generation of free radicals. Additionally, curcuminoids are known to absorb UV rays and to protect pharmaceutical preparations from physio-chemical deterioration. Curcuminoids have also been found to prevent pyrolysis which is the high temperature related deterioration of processed food and nutrients. Curcuminoids are also recognized for their anti-microbial properties in preventing the growth of bacteria or fungi, which is a factor that is detrimental to the stability of lutein and lutein esters especially in humid conditions. Tetracurcuminoids, which are derivatives of curcuminoids, are particularly effective in scavenging free radicals and are also complementary to the action of curcuminoids which are primarily effective in preventing free radicals from occurring in biological systems. Carnosic acid is compatible and complementary with both curcuminoids and tetracurcuminoids. It is an antioxidant and anti-microbial compound similar to curcuminoids and tetracurcuminoids' broad action consisting of free radical prevention and scavenging action.
- The process of obtaining XENOGARD lutein and lutein esters proceeds as follows. First, marigold flower petals are harvested. These petals are then shade dried, crushed and left at room temperature for a period of time, preferably 3 to 4 hours. The resulting material is then treated with a solvent, preferably an alcohol, and more preferably ethyl alcohol, and incubated, preferably for 5 hours at room temperature. A preferable ratio of solvent to marigold flower petals is 100 kg of the marigold material to 400 L of ethyl alcohol. Following the incubation period, the resulting solution is collected. This procedure is then repeated, preferably at least two additional times, and the combined alcohol extracts are combined. If the process is repeated two times and the preferred ratio is used then the total solution should amount to about 1250 L. The extracts are then diluted with water to obtain an alcohol solution, which is preferably 70% by weight alcohol.
- Alternatively, the shade dried petals can be treated with supercritical carbon dioxide for a period of time, preferably 10 hours, and after the evaporation of the carbon dioxide occurs, the remaining oleoresin is diluted with an alcohol, preferably ethanol, and water, as described above, to obtain a diluted alcohol solution, preferably a 70% alcohol solution.
- This extract of marigold petals in the alcohol solution may then used to obtain lutein esters or free lutein by subjecting the extract to hydrolysis. This process entails passing the oleoresin in the alcohol solution through a column packed with an anion exchange resin. Preferably, this is performed at a rate of 20-50 L per hour. Suitable resins include Amberjet 4200(c), Amberlite IRA 410, Amberlite IRA 900, Dowex 1x2-100, Dowex 22cl, Dowex Marathon A2,
Dowex MSA 1, Dowex 550 A, all of which are Rohm-Haas or Dow products. - Upon completion of the hydrolysis, the eluents are collected and diluted with deionized water with a strong and vigorous agitation. The resulting lutein crystals are filtered, collected, and dried in vacuum with the exclusion of oxygen.
- These lutein crystals or lutein esters can be combined subsequent to their isolation with a stabilizing mixture of tetrahydrocurcuminoids in an amount of 0.01-10.0 wt %, curcuminoids in an amount of 0.01-10.0 wt %, and carsonic acid in an amount of 0.01-10.0 wt % to form the XENOGARD composition. Preferably each of the stabilizing ingredients are present in an amount of 0.1 wt. %. The XENOGARD composition of lutein or esters of lutein are then packaged under nitrogen atmosphere, sealed, and stored until further use. An additional XENOGARD compositions of lutein and lutein esters can be prepared in the form of a soft extract comprising at least 50 wt % marigold oleoresin, 45 wt % vegetable oil (preferably refined Soya oil), 1.5 wt % citric acid, and 2 wt % natural tocopherol.
- The XENOGARD lutein and lutein esters can be further stabilized by a coating process. An example of such a coating process would involve combining a sugar, preferably sucrose, preferably in as slurry form, with water (preferably distilled water) and the XENOGARD composition to obtain a uniform blend. Preferably, the ratio used in forming the uniform blend would entail 450 g of sucrose to 100 ml of distilled water to 250 mg of the XENOGARD composition. Starch is then added to the uniform blend and the resulting mixture is then charged to a mixer which is run until the mixture is blended, preferably 30 minutes. Also, the preferred ratio used in determining the appropriate amount of starch to add is 630 g of starch to 800 g of the uniform blend. PVP (preferably in a ratio 450 g to 1430 g of starch solution) combined in a solvent (preferably 70% ethanol solution) is then added to the starch solution and blended to form a dough with a preferred moisture content of less than 5%, adjusted at 30° C. under vacuum. The dough is then fed into a granulator preferably fitted with a 30 mesh screen and the granules are collected in trays which have been preferably lubricated with talc and dried under a vacuum for 8-12 hours. The dried granules are then transferred to a coating pan (suitably approximately 350 g of PVP and 40 g of paprika resin). The resulting granules are dried again under vacuum at 30° C. for about 6-8 hours, and sifted and packed.
- An example of a XENOGARD product is Zealutein®. Zealutein® is comprised of lutein, zexanthin, piperine (Bioperine®)), other carotenoids, and other stabilizing components. FIG. 1 proves Zealutein®'s antioxidant activities, whereas FIGS. 2 and 3 illustrate its stability in two different forms. Further, it has been shown that the Zealutein® Regular Granules are stable for three years under normal conditions, whereas Zealutein® BJ-80 Mesh is stable for two years under normal conditions. The composition of both of these forms of Zealutein® are disclosed in FIGS. 4 and 5. However, the final composition of Zealutein® comprises lutein in an amount not less than 5 weight percent of the final product, Zeaxanthin in an amount not less than 1 weight percent of the final product, Piperine (and prefereably Bioperin®) in an amount not less than 2 weight percent of the final product, and other carotenoids in an amount not less than 1 weight percent of the final product.
- Additionally, further stabilizing components which may be used in the present invention include other carotenoids in the form of Capsanthin ester, Capsorubin ester, Zeaxanthin ester, Cryptoxanthin exter, and beta-carotene ester. These stabilizing components may be 1-10 weight percent of the final product. Additionally, paprika carotenoids are a potential source of stabilizing components, provided the paprika carotenoids are in the form of esters. Additions to the stabilizing components may also be added. These added compounds include tetracurcuminoids, Rosmarinic acid, green tea catechins and other similar natural antioxidants.
- FIG. 1: FIG. 1 illustrates the Rancimat testing of Zealutein® and shows that Zealutein® possesses antioxidant properties.
- FIG. 2: FIG. 2 illustrates a comparison of Zealutein® Regular Granules against lutein in which the stability of each has been tested at 30 day intervals in conditions of 40° C. and 75% relative humidity.
- FIG. 3: FIG. 3 illustrates a comparison of Zealuteine BJ-80 Mesh against lutein in which the stability of each has been tested at 30 day intervals in conditions of 40° C. and 75% relative humidity.
- FIG. 4: FIG. 4 lists the requirements and composition for Zealuteine BJ-80 Mesh.
- FIG. 5: FIG. 5 lists the requirements and composition for Zealutein® Regular Granules.
- FIG. 6: FIG. 6 illustrates the results of testing the effect of a topical application of zealutein on 12 O-tetradecanoylphorbol-13-acetate (TPA)-induced edema of mouse ears.
- FIG. 7: FIG. 7 illustrates the dramatic difference in the percent of mice with cancer when being treated with a topical application of TPA when one group is treated with TPA alone and another is treated with TPA and zealutein.
- FIG. 8: FIG. 8 illustrates the results of testing the inhibitory effect of zealutein on 12 O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor promotion in CD-1 mice previously initiated with 7,12-dimethylbenz[a]anthracene (DBMA).
- Sies, H., Stahl, W., Sundquist, A. R. (1992) Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids. Ann. N.Y. Acad. Sci., 669, 7-20.
- Chew, B. P., Wong, M. W., and Wong, T. S. (1996) Effects of lutein from marigold extract on immunity and growth of mammary tumors in mice. Anticancer Res., 16, 3689-3694.
- Jyonouchi, H., Zhang, L., Gross, M. and Tomita, Y. (1994) Immunomodulating actions of carotenoids: Enhancement of in vivo and in vitro antibody production to T-dependent antigens. Nutr. Cancer, 21(1), 47-58.
- Shi, X. M. and Chen, F. (1997) Stability of lutein under various storage conditions Nahrung, 44, 38-41.
- Sapozhnikov, D. I., Eidelman, Z. M., Bazhanova, N. V., and Popova, O. F. (1959) Blocking of the light reaction by hydroxylamine in the transformation of xanthophylls. Doklady. Akad. Nauk. SSSR., 127,1128-1131; Chem Abstr., 54, 11162.
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Claims (36)
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US10/058,827 US6689400B2 (en) | 2001-01-30 | 2002-01-30 | Process of obtaining compositions of stable lutein and lutein derivatives |
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US26472201P | 2001-01-30 | 2001-01-30 | |
US10/058,827 US6689400B2 (en) | 2001-01-30 | 2002-01-30 | Process of obtaining compositions of stable lutein and lutein derivatives |
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US20030018222A1 true US20030018222A1 (en) | 2003-01-23 |
US6689400B2 US6689400B2 (en) | 2004-02-10 |
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US10/058,827 Expired - Lifetime US6689400B2 (en) | 2001-01-30 | 2002-01-30 | Process of obtaining compositions of stable lutein and lutein derivatives |
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US (1) | US6689400B2 (en) |
EP (1) | EP1355877A1 (en) |
JP (1) | JP4227409B2 (en) |
WO (1) | WO2002060864A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030228392A1 (en) * | 2002-06-06 | 2003-12-11 | Wyeth | Infant formula compositions containing lutein and zeaxanthin |
US20050031736A1 (en) * | 2001-12-12 | 2005-02-10 | Nguyen Minhthy Le | Infant formulas containing lutein compounds |
Families Citing this family (15)
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US6936279B2 (en) * | 2002-06-18 | 2005-08-30 | Zeavision Llc | Microcrystalline zeaxanthin with high bioavailability in oily carrier formulations |
ATE359266T1 (en) * | 2002-09-20 | 2007-05-15 | Riken Vitamin Co | METHOD FOR PURIFYING MARIGOLD OLEORESIN |
US7541166B2 (en) * | 2003-09-19 | 2009-06-02 | Microfluidic Systems, Inc. | Sonication to selectively lyse different cell types |
RU2321582C2 (en) * | 2004-01-16 | 2008-04-10 | Индэс Байотек Прайвет Лимитед | Method for preparing stable lutein paste from essential oil |
GB0501365D0 (en) * | 2005-01-21 | 2005-03-02 | Promar As | Compositions |
US8592662B2 (en) | 2005-02-11 | 2013-11-26 | Kalamazoo Holdings, Inc. | Capsicum variety exhibiting a hyper-accumulation of zeaxanthin and products derived therefrom |
EP2329815A1 (en) | 2005-02-11 | 2011-06-08 | Kalamazoo Holdings, Inc. | A capsicum variety exhibiting a hyper-accumulation of zeaxanthin and products derived therefrom |
JP4489721B2 (en) * | 2005-04-25 | 2010-06-23 | 富士フレーバー株式会社 | Extraction method of flavor vegetable extract |
KR101016104B1 (en) | 2008-04-10 | 2011-02-17 | (주)엠에스토피아 | Microorganism composition using as feed additives for production of lutein rich egg |
AU2010200636B2 (en) * | 2009-04-27 | 2015-05-28 | Katra Phytochem (India) Private Limited | A process for isolation of carotenoids from plant sources |
US9290433B2 (en) | 2011-01-17 | 2016-03-22 | India Glycols Limited | Single stage lutein ester extraction from tagetes species-marigold flower meal |
JP2014529607A (en) | 2011-08-26 | 2014-11-13 | ピーティーティー グローバル ケミカル パブリック カンパニー リミテッド | Method for extracting lutein / xanthophyll from natural substances and highly purified lutein / xanthophyll obtained by this method |
CN102887848A (en) * | 2012-10-30 | 2013-01-23 | 长沙芬康生物科技有限公司 | Method for preparing lutein crystals from marigold ointment by catalytic saponification |
BR112015014187B8 (en) | 2012-12-19 | 2022-08-30 | Novus Int Inc | COMPOSITION OF XANTHOPHYL, ITS USE, ANIMAL FEED AND METHODS OF INCREASE THE PIGMENTATION EFFECTIVENESS AND THE CAROTENOID CONTENT OF THE FOOD |
KR102161387B1 (en) * | 2019-12-09 | 2020-09-29 | 대한켐텍 주식회사 | A composition comprising lutein for improving skin condition and a fuctional food comprising the composition |
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US3998753A (en) * | 1974-08-13 | 1976-12-21 | Hoffmann-La Roche Inc. | Water dispersible carotenoid preparations and processes thereof |
US4048203A (en) * | 1976-12-06 | 1977-09-13 | Thomas Philip | Purification of lutein-fatty acid esters from plant materials |
IL88961A (en) * | 1988-01-29 | 1992-07-15 | Basf Ag | Stable mixtures containing oxidation-sensitive compounds |
US5017397A (en) * | 1990-04-25 | 1991-05-21 | Uy Nguyen | Process for extracting antioxidants from Labiatae herbs |
CH685189A5 (en) * | 1993-11-19 | 1995-04-28 | Marigen Sa | Ultramicroemulsions spontaneously dispersible concentrates with antitumoral effective xanthophyll esters. |
US5382714A (en) * | 1994-03-17 | 1995-01-17 | The Catholic University Of America | Process for isolation, purification, and recrystallization of lutein from saponified marigold oleoresin and uses thereof |
US5744161A (en) * | 1995-02-24 | 1998-04-28 | Sabinsa Corporation | Use of piperine as a bioavailability enhancer |
US5648564A (en) * | 1995-12-21 | 1997-07-15 | Kemin Industries, Inc. | Process for the formation, isolation and purification of comestible xanthophyll crystals from plants |
US6007856A (en) * | 1997-08-08 | 1999-12-28 | The Procter & Gamble Company | Oil-in-water dispersions of β-carotene and other carotenoids stable against oxidation prepared from water-dispersible beadlets having high concentrations of carotenoid |
AU1271999A (en) * | 1997-10-21 | 1999-05-10 | Office Of Technology Liaison | Process for extraction and purification of lutein, zeaxanthin and rare carotenoids from marigold flowers and plants |
US5972993A (en) * | 1998-03-20 | 1999-10-26 | Avon Products, Inc. | Composition and method for treating rosacea and sensitive skin with free radical scavengers |
-
2002
- 2002-01-30 EP EP02702091A patent/EP1355877A1/en not_active Ceased
- 2002-01-30 JP JP2002561015A patent/JP4227409B2/en not_active Expired - Lifetime
- 2002-01-30 US US10/058,827 patent/US6689400B2/en not_active Expired - Lifetime
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050031736A1 (en) * | 2001-12-12 | 2005-02-10 | Nguyen Minhthy Le | Infant formulas containing lutein compounds |
US20030228392A1 (en) * | 2002-06-06 | 2003-12-11 | Wyeth | Infant formula compositions containing lutein and zeaxanthin |
WO2003103646A1 (en) * | 2002-06-06 | 2003-12-18 | Wyeth | Infant formula compositions containing lutein and zeaxanthin |
AU2003251396B2 (en) * | 2002-06-06 | 2007-12-20 | Société des Produits Nestlé S.A. | Infant formula compositions containing lutein and zeaxanthin |
SG165985A1 (en) * | 2002-06-06 | 2010-11-29 | Wyeth Corp | Infant formula compositions containing lutein and zeaxanthin |
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JP4227409B2 (en) | 2009-02-18 |
EP1355877A1 (en) | 2003-10-29 |
US6689400B2 (en) | 2004-02-10 |
WO2002060864A1 (en) | 2002-08-08 |
JP2004518682A (en) | 2004-06-24 |
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